Involvement of COX-1 in A3 adenosine receptor-mediated contraction through endothelium in mice aorta
Involvement of COX-1 in A3 adenosine receptor-mediated contraction through endothelium in mice aorta
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DOI：
10.1152/ajpheart.00764.2007
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发表时间：
2007-12-01
影响因子：
4.8
通讯作者：
Mustafa, S. Jamal
中科院分区：
文献类型：
--
作者：
Ansari, Habib R.;Nadeem, Ahmed;Mustafa, S. Jamal
我们利用野生型（WT）和A(3)敲除型（A(3)KO）小鼠主动脉研究了A(3)腺苷受体（A(3)AR）是否通过环氧化酶（cox）参与内皮介导的收缩。A(3) ar选择性激动剂C1-IBMECA在内皮（+E）完整的WT小鼠主动脉中产生浓度依赖性收缩（EC50: 2.9 +/- 0.2 x 10(-9) M），而在A(3)KO +E主动脉中的作用可以忽略不计。在10(-7)M时，C1-IBMECA产生的收缩在WT +E中为29%，而在A(3)KO +E中不明显。在WT和A(3)KO主动脉中，内皮剥脱组织（-E）中c1 - ibmeca诱导的反应被消除。与WT +E主动脉相比，WT -E中A(3)AR基因和蛋白表达分别降低了74%和72% (P < 0.05)，而在A(3)KO +E/-E主动脉中未检测到。吲哚美辛（非特异性cox阻滞剂，10(-5)M）、SC-560（特异性COX-1阻滞剂，10(-8)M）、SQ 29549（血栓素前列腺素受体拮抗剂，10(-6)M）和fureclate（血栓素合成酶抑制剂，10(-5)M）显著抑制c1 - ibmeca诱导的收缩。吲哚美辛、SC-560和fureglate在WT +E主动脉中也能显著减少c1 - ibmeca诱导的血栓素B-2的产生，而在A(3)KO +E主动脉中的作用可以忽略不计。NS-398（特异性COX-2阻滞剂）对c1 - ibmeca诱导的WT +E和A(3)KO +E主动脉收缩的抑制作用可忽略不计。WT +E主动脉特异性a (3)AR拮抗剂MRS1523显著抑制c1 - ibmeca诱导的COX-1和血栓素前列腺素受体表达的增加。A(3)AR和COX-1的表达主要位于WT和A(3)KO +E主动脉内皮。这些结果首次证明COX-1途径参与了A(3) ar介导的内皮细胞收缩。
We investigated whether A(3) adenosine receptor (A(3)AR) is involved in endothelium-mediated contraction through cyclooxygenases (COXs) with the use of wild-type (WT) and A(3) knockout (A(3)KO) mice aorta. A(3)AR-selective agonist, C1-IBMECA, produced a concentration-dependent contraction (EC50: 2.9 +/- 0.2 x 10(-9) M) in WT mouse aorta with intact endothelium (+E) and negligible effects in A(3)KO +E aorta. At 10(-7) M, contractions produced by C1-IBMECA were 29% in WT +E, while being insignificant in A(3)KO +E aorta. C1-IBMECA-induced responses were abolished in endothelium-denuded tissues (-E), in both WT and A(3)KO aorta. A(3)AR gene and protein expression were reduced by 74 and 72% (P < 0.05), respectively, in WT -E compared with WT +E aorta, while being undetected in A(3)KO +E/-E aorta. Indomethacin ( nonspecific COXs blocker, 10(-5) M), SC-560 (specific COX-1 blocker, 10(-8) M), SQ 29549 (thromboxane prostanoid receptor antagonist, 10(-6) M), and furegrelate (thromboxane synthase inhibitor, 10(-5) M) inhibited C1-IBMECA-induced contraction significantly. C1-IBMECA-induced thromboxane B-2 production was also attenuated significantly by indomethacin, SC-560, and furegrelate in WT +E aorta, while having negligible effects in A(3)KO +E aorta. NS-398 (specific COX-2 blocker) produced negligible inhibition of C1-IBMECA-induced contraction in both WT +E and A(3)KO +E aorta. C1-IBMECA-induced increase in COX-1 and thromboxane prostanoid receptor expression were significantly inhibited by MRS1523, a specific A(3)AR antagonist in WT +E aorta. Expression of both A(3)AR and COX-1 was located mostly on endothelium of WT and A(3)KO +E aorta. These results demonstrate for the first time the involvement of COX-1 pathway in A(3)AR-mediated contraction via endothelium.